1. Field of the Invention
The present invention relates to sulfonamide derivatives, more specifically, to novel sulfonamide derivatives represented as the following general formula (I), useful as matrix metalloproteinase inhibitor and pharmaceutically acceptable salts thereof and a process for preparing the compounds. 
2. Description of the Prior Art
Matrix metalloproteinase (xe2x80x9cMMPxe2x80x9d) is a Ca2+-dependent proteinase containing zinc ion (Zn2+) at its active site. At least, more than 18 matrix metalloproteinases including stromelycin, collagenase and a family of gelatinase have been identified. MMP degrades various extracellular matrix components of collagen, laminin, proteoglycan, fibronectin, elastin and gelatin under physiological conditions and, therefore, are effective on growth and tissue remodeling of articulation tissue, bone tissue, and connective tissue. The MMP contains Zn2+ at its active site and has Ca2+-dependent activity. They are secreted as an inactive form of proenzyme, which is subsequently activated in extracellular side, together with a naturally occuring inhibitor, TIMP (tissue inhibitor of metalloproteinase)
Meanwhile, MMP inhibitor is useful to prevention and treatment of all sorts of diseases caused by overexpression or overactivation of MMP. Such diseases are, for example, rheumatoid, arthrosteitis, unusual bone resorption, osteoporosis, periodontitis, interstitial nephritis, arteriosclerosis, pulmonary emphysema, cirrhosis, cornea injury, metastasis, invasion or growth of tumor cell, autoimmune disease, disease caused by vascular emigration or infiltration of leukocytes, arterialization (see: Beeley et al., Curr. Opin. Ther. Patents, 4(1):7-16, 1994). For instance, it was reported that synthetic MMP inhibitor has an anti-cancer activity in vivo along with inhibition of basement membrane remodeling in the mouse model bearing ovarian cancer (see: Cancer Res., 53:2087, 1993). Particularly, considering the fact that MMP-2 and MMP-9 among the above MMP enzymes play an essential role in angiogenesis required for the growth of cancer cells (see: Biochim. Biophys. Acta, 695, 1983), and that MMP-1 and MMP-3 among MMP enzymes play an important role in the progress of arthritis as observed in much higher concentration than normal in the synovium and cartilage of a patient of rheumatoid arthritis (see: Arthritis Rheum., 35:35-42, 1992), the selectivity to MMP-1/MMP-2 is considered to play a crucial role in reducing side effects such as arthralgia. Therefore, researches have been made while focusing on the development of selective inhibitors, and many MMP inhibitors have been designed and synthesized in many aspects (see: J. Enzyme Inhibitor, 2:1-22, 1987; Current Medicinal Chemistry, 2:743-762, 1995; Progress in Medicinal Chemistry, 29:271-334, 1992; Exp. Opin. Ther. Patents, 5:1287-1296, 1995; Drug Discovery Today, 1:16-26, 1996; Chem. Rev., 99:2735-2776, 1999).
Some compounds possessing inhibitory activity against MMP are known. In general, they have a zinc binding group (xe2x80x9cZBGxe2x80x9d), which is coordinated to the zinc ion of MMP enzymes at the active site of them. Such ZBGs include hydroxamic acid, carboxylic acid, phosphoric acid, phosphinic acid, thiol and so forth (see: WO 92/09564; WO 95/04033; WO 00/04030; WO 00/43404; WO 95/13289; WO 96/11209; WO 95/09834; WO 95/09620; WO 00/40577; WO 00/40600; WO 98/03166; Chem. Rev. 99:2735-2776, 1999). Especially, several kinds of succinic acid derivatives based on substrate backbone have been designed and synthesized as a peptide-mimic inhibitor. (see: WO 99/25693; WO 98/43959; WO 98/24759; WO 98/30551; WO 98/30541; WO 97/32846; WO 99/01428; EP 897908; WO 98/38179; JP 95002797; WO 99/18074; WO 99/19296; EP 641323). The peptide-mimic inhibitors are known to contain a hydroxamic acid as a ZBG and display a broad spectrum for MMP enzymes.
However, some of the above peptide-mimic inhibitors are often poorly absorbed, exhibiting low oral bioavailability. They are also subject to rapid proteolytic metabolism, thus having short half-life. Furthermore, they possess lower selectivity to MMP-1/MMP-2 and induce the side effect of arthralgia in clinical trial (see: Current Pharmaceutical Design, 5:787-819, 1999; Current Opinion in Drug Discovery and Development, 3:353-361, 2000; Drugs of the Future, 21(12) :1215-1220, 1996).
In 1996, non-peptide inhibitors was developed to solve the said problems which are substantially distinguished in terms of chemical structure from the above peptide-mimic inhibitors having simple sulfonyl amino acid derivative represented as a chemical formula below (see: U.S. Pat. No. 5,506,242; J. Med. Chem., 40:2525-2532, 1997). 
Under a consideration that the small molecule of sulfonamide-derived MMP inhibitors have strong activities in vitro against MMP enzymes, and have advantages over the said peptide-mimic inhibitors, a variety of sulfonamide inhibitors have been synthesized and reported in the literature (see: WO 98/50348; WO 97/20824; WO 00/09485; WO 99/58531; WO 99/51572; WO 99/52889; WO 99/52910; WO 99/37625; WO 98/32748; WO 99/18076; WO 99/06410; WO 99/07675; WO 98/27069; WO 97/22587; EP 979816; EP895988; EP 878467; EP 1041072) To improve in vitro enzymatic activity, selectivity, and pharmacokinetic profiles, new sulfonamide derivatives have been designed and synthesized, by changing P1xe2x80x2 of the above sulfonamide inhibitor which binds to S1xe2x80x2 sub-site of the enzymes. 
However, while the above sulfonamide inhibitors have relatively high inhibitory activity against MMP, they do not have a higher selectivity to MMP-1/MMP-2 as compared with previous peptide-mimic inhibitors. Some of them have also side effect of arthralgia in clinical trials (see: Current Pharmaceutical Design, 5:787-819, 1999; Current Opinion in Drug Discovery and Development, 3:353-361, 2000; Exp. Opin. Invest. Drugs, 9:2159-2165, 2000; Drugs of the Future, 24(1):16-21, 1999). Although the sulfonamide inhibitors containing a hydroxamic acid as a ZBG typically showed a very strong in vitro inhibitory activity as compared with those containing a carboxylic acid as a ZBG, they also have revealed a limitation in oral administration due to their lower bioavailability and lower metabolic stability in vivo (see: J. Med. Chem., 41:640-649, 1988; Investigational New Drugs 16:303-313, 1999; Exp. Opin. Ther. Patents, 10:111-115, 2000; WO 00/63194; WO 00/27808; WO 99/18079; U.S. Pat. No. 6,117,869).
Under the circumstance, there are strong reasons for developing alternative compounds whose inhibitory action on MMP and the selectivity to MMP-1/MMP-2 are increased to reduce side effects.
The present inventors have made an effort to develop a new compound in which the inhibitory action on MMP and the selectivity to MMP-1/MMP-2 are increased to reduce side effects, and finally found that a new synthetic inhibitor of sulfonamide derivatives selectively inhibit MMP activity in vitro.
A primary object of the present invention is, therefore, to provide a sulfonamide derivative inhibiting MMP activity.
The other object of the invention is to provide a process for preparing the said derivative.
The present invention provides a sulfonamide derivative, which inhibits MMP activity, represented as the following general formula (I), the isomers and the pharmaceutically acceptable salts thereof, and a process for preparing the above compounds. 
wherein,
R1 denotes hydrogen, C1-12 alkyl, carbocyclic aryl-lower alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-lower alkyl, (oxo, amino or thio) C3-7 cycloalkyl, (oxo, amino or thio) C3-7 cycloalkyl-lower alkyl, C2-12 lower alkenyl, C2-12 lower alkynyl, carbocyclic aryl, heterocyclic aryl, heterocyclic aryl-lower alkyl, biaryl, halo lower alkyl, biaryl-lower alkylarylalkyl, hydroxy-lower alkyl, alkoxyalkyl, acyloxy-lower alkyl, alkyl or aryl (thio, sulfinyl or sulfonyl) lower alkyl, (amino, mono or dialkylamino) lower alkyl, acylamino lower alkyl, (N-lower alkyl-piperazino, or N-carbocyclic or heterocyclic aryl-lower alkyl piperazino)-lower alkyl or (morpholino, thiomorpholino, piperidino, pyrrolidino or piperidyl)-lower alkyl;
R2 denotes hydrogen, lower alkyl, carbocyclic aryl-lower alkyl, C1-4 carbocyclic aryl-lower alkyl, C1-4 heterocyclic aryl-lower alkyl, C1-5 alkoxyphenyl-lower alkyl, C1-5 alkenoxyphenyl-lower alkyl, C1-5 alkynoxyphenyl-lower alkyl, heterocyclic aryl-lower alkyl, hydroxy-lower alkyl, alkoxyalkyl, acyloxy-lower alkyl, thio-lower alkyl, alkyl or aryl-(thio, sulfinyl or sulfonyl) lower alkyl, (amino, mono or dialkylamino) lower alkyl, carboxyl-lower alkyl, (amino, mono or dialkylamino) lower alkyl or acylamino lower alkyl;
R3 denotes hydrogen or C1-6 lower alkyl;
R4 denotes hydrogen, C1-12 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-lower alkyl, (oxo, amino or thio) C3-7 cycloalkyl, (oxo, amino or thio) C3-7 cycloalkyl-lower alkyl, carbocyclic aryl, carbocyclic aryl-lower alkyl, heterocyclic aryl, heterocyclic aryl-lower alkyl, biaryl, biaryl-lower alkyl, halo lower alkyl, hydroxy-lower alkyl, alkoxyalkyl, acyloxy-lower alkyl, alkyl or aryl-(thio, sulfinyl or sulfonyl) lower alkyl, (amino, mono or dialkylamino) lower alkyl, acylamino lower alkyl, carboxyl lower alkyl, (N-lower alkyl-piperazino, or N-carbocyclic or heterocyclic aryl piperazino)-lower alkyl or (morpholino, thiomorpholino, piperidino, pyrrolidino or piperidyl)-lower alkyl;
R5 denotes hydroxy, alkoxy, halogen, thiol, thioalkoxy or hydroxylamine; and,
X1 and X2 denote Nxe2x80x94R7 (wherein, R7 is hydrogen, C1-6 lower alkyl, aryl, heteroaryl or arylalkyl), S or O.
Otherwise mentioned, all kinds of isomers of the above sulfonamide compounds are fallen within the scope of the invention. For instance, in case of alkyl, alkoxy alkene and alkyne, compounds of the invention include isomers due to an asymmetric carbon atom as well as the straight- and branched-chains thereof.
The pharmaceutically acceptable salts of the invention include acid-added salts and hydrates. In general formula (I), the compound of the invention can be converted to the salts corresponding to them, preferably alkali metal salts (sodium, potassium, etc.), alkaline earth metal salts (calcium, magnesium, etc.), ammonium salts, non-toxic salts of pharmaceutical organic amine and water-soluble salts. The compound of the general formula (I) can be converted to inorganic acid salts (hydrochloride, hydrogen bromide, hydrogen iodide, sulfate, phosphate, nitrate, etc.) and organic acid salts (acetate, lactate, tartarate, oxalate, fumarate, glucuronate, etc.), preferably non-toxic salts and water-soluble salts. The compound of the general formula (I) and its salts can be also converted to the hydrates corresponding to them by the conventionally method in the art.
Among the compounds of general formula (I), a cyclic compound may be formed by the linkage of the above defined R2 and R3, which is represented as the general formula (I-1), and a cyclic compound formed by the linkage of R2 and R4, which is represented as the general formula(I-2). 
wherein,
R1, R3, R4, R5, X1 and X2 are the same as defined in the general formula (I) above; and,
n is an integer of 0 to 4.
Each of the above cyclic compounds can contain hetero-atoms of one or two nitrogens, oxygens, sulfurs, etc.
Two processes for preparing the compounds of the general formula (I) are illustrated by the following steps, which may be applied to the preparation of the compounds, depending physical and chemical properties of R1.
Process 1: In a case that R1 does not have an aromatic ring and the carbon which is directly linked with X2 is a primary carbon
Step 1: Synthesis of Intermediate Compound (IV)
An amino acid derivative (III) is reacted with a sulfonyl halide (II) in an organic solvent in the presence of a base to give an intermediate compound(IV): The organic solvent includes most of non-protic solvents, preferably, dichloromethane or dichloroethane, and the base includes triethylamine or N-methylmorpholine.
Step 2: Introduction of R4 Group
The intermediate compound (IV) is reacted with R4-L (L: reactive leaving group) in an organic solvent in the presence of a base to give an intermediate compound (V): The organic solvent preferably includes DMF, THF or MeCN, and the base includes K2CO3, NaHCO3, t-BuOH, NaH, etc.
Step 3: Deprotection of Intermediate Compound (V)
A protecting group of amino acid, R6, is removed from the intermediate compound (V) by the hydrolysis in the presence of a base or an acid, or by subjecting in various conditions of H2/Pdxe2x80x94C, KF, etc. to give the compound of the general fomula (I): The base preferably includes NaOH, KOH, LiOH, K2CO3, etc. and the acid preferably includes HCl, CF3CO2H, etc. In the case that R6 is silyl group, it is removed by heating the intermediate compound (V) in the presence of Fxe2x88x92 of HF, KF, TBAF, etc. or methanol. Optionally, a condensation reaction with hydroxylamine is carried out generally by activating the acid of intermediate compound (V), and reacting with hydroxylamine. The activation of the acid can be made by acid chloride method, mixed anhydride method, active ester method, etc. (see: J. Med. Chem., 40: 2525-2532, 1997; J. Med. Chem., 41:640-649, 1998). 
wherein,
R1, R2, R3, R4, X1 and X2 are the same as defined in the general formula (I) above; and,
R6 is a substituent used as a protecting group of amino acid, such as hydrogen, methyl, ethyl, t-butyl, benzyl, diphenylmethyl or silyl group.
Meanwhile, sulfonyl halide (II) employed as a starting material is prepared as follows: 
Step 1: Preparation of Compound (XIII)
A compound (XII) is subjected to substitution reaction with alkylhalide using an inorganic salt or organic salt at a room temperature to 100xc2x0 C. in an organic solvent to prepare a compound (XIII): The compound (XII) preferably includes 2-mercaptobenzthiazol, 2-mercaptobenzoxazol, hydroxybenzthiazol, hydroxybenzoxazol, halobenzthiazol or halobenzoxazol, and the organic solvent is preferably a mixed solution of water and water-miscible organic solvents.
Step 2: Preparation of Sulfonyl Halide (II)
Chlorosulfonylation of a compound (XIII) is accomplished by the conventionally known methods below or the partially modified methods (see: U.S. Pat. No. 4,820,332, U.S. Pat. No. 5,504,098, U.S. Pat. No. 5,985,870, U.S. Pat. No. 5,559,081, EP 168264, U.S. Pat. No. 5,973,148, U.S. Pat. No. 5,962,490): For example, chlorosulfonylation of a compound (XIII) is made by reacting the compound (XIII) at a temperature of 50 to 130xc2x0 C. in an organic solvent of dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc., or without organic solvent, in the presence of 2.5 to 5.0 volumes of chlorosulfonic acid. Also, in the reaction, though it is variable depending on the R1, 2-substituted sulfonic acid (XIV) is obtained as a product along with 2-substituted sulfonylchloride (II) in the form of mixture. Without an isolating step, the mixture is treated with a chlorination reagent of SOCl2, POCl3, PCl3, etc. to obtain 2-substituted sulfonylchloride (II) only, or the mixture is isolated by recrystallization to give a pure 2-substituted sulfonic acid (XIV) which is then treated with a chlorination reagent of SOCl2, POCl3, PCl3, etc. to be converted into 2-substituted sulfonylchloride (II).
In the Process 1 above, if the compound (III-1) is employed instead of the amino acid derivative (III), a cyclic compound formed by the linkage of R2 and R3 is prepared as follows, where the compound (III-1) is obtained commercially or prepared by the conventionally known methods (see: WO 9952889; EP 1041072): 
wherein,
R1, R4, X1, and X2 are the same as defined in the general formula (I) above;
R6 is a substituent used as a protecting group of amino acid, such as hydrogen, methyl, ethyl, t-butyl, benzyl, diphenylmethyl or silyl group; and,
n is an integer of 0 to 4.
Also, if the compound (III-2) is employed instead of the amino acid derivative (III), a cyclic compound formed by the linkage of R2 and R4 is prepared as follows, where the compound (III-2) is obtained commercially or prepared by conventionally known methods (see: U.S. Pat. No. 5,861,510; U.S. Pat. No. 5,753,635; WO 97/20824; WO 98/08814; EP 803505; WO 98/08815; WO 98/08825; WO 98/08850; WO 98/50348; EP 878467): 
wherein,
R1, R3, X1 and X2 are the same as defined in the general formula (I) above;
R6 is a substituent used as a protecting group of amino acid, such as hydrogen, methyl, ethyl, t-butyl, benzyl, diphenylmethyl or silyl group; and,
n is an integer of 0 to 4.
Process 2: In a case that R1 have an aromatic Ring, or the carbon which is directly linked with X2 is a secondary carbon or contains a hetero atom 
wherein,
R1, R2, R3, R4, X1 and X2 are the same as defined in the general formula (I) above; and,
R6 is a substituent used as a protecting group of amino acid, such as hydrogen, methyl, ethyl, t-butyl, benzyl, diphenylmethyl or silyl group.
Step 1: Synthesis of Sulfonylchloride
The compound (VI) is subjected to the chlorosulfonylation reaction to give a compound (VII).
Step 2: Synthesis of an Intermediate Compound (VIII)
An amino acid derivative (III) is reacted with the above compound (VII) in an organic solvent in the presence of a base to give an intermediate compound (VIII): The organic solvent includes almost all of non-protic solvents, preferably, dichloromethane or dichloroethane, and the base includes triethylamine or N-methylmorpholine.
Step 3: Substitution of the Intermediate Compound (VIII) with R1xe2x80x94X2H
The intermediate compound (VIII) is reacted with R1xe2x80x94X2H at a temperature of 70 to 80xc2x0 C. in an organic solvent in the presence of a base to give an intermediate compound (IV): The organic solvent preferably includes MeCN, THF or DMF, and the base preferably includes K2CO3 or NaHCO3.
Step 4: Introduction of R4 
The intermediate compound (IV) is reacted with R4-L (L:reactive leaving group) in an organic solvent in the presence of a base to give an intermediate compound (V): The organic solvent preferably includes DMF, THF or MeCN, and the base includes K2CO3, NaHCO3, t-BuOH, NaH, etc.
Step 5: Deprotection of Intermediate Compound (V)
A protecting group of amino acid, R6, is removed from the intermediate compound (V) by the hydrolysis in the presence of a base or an acid or by subjecting in various conditions of H2/Pdxe2x80x94C, KF, etc. to give the compound of the general formula (I): The base preferably includes NaOH, KOH, LiOH, K2CO3, etc. and the acid preferably includes HCl, CF3CO2H, etc. In the case that R6 is silyl group, it is removed by heating the intermediate compound (V) in the presence of Fxe2x88x92 of HF, KF, TBAF, etc. or methanol. Optionally, a condensation reaction with hydroxylamine is carried out generally by activating the acid of intermediate compound (V), and reacting with hydroxylamine. The activation of the acid can be made by acid chloride method, mixed anhydride method, active ester method, etc. (see: J. Med. Chem., 40: 2525-2532, 1997; J. Med. Chem., 41:640-649, 1998).
The present invention is further illustrated in the following examples, which should not be taken to limit the scope of the invention.